The role and control of arginine levels in arginase 1 deficiency

Abstract

Arginase 1 Deficiency (ARG1-D) is a rare urea cycle disorder that results in persistent hyperargininemia and a distinct, progressive neurologic phenotype involving developmental delay, intellectual disability, and spasticity, predominantly affecting the lower limbs and leading to mobility impairment. Unlike the typical presentation of other urea cycle disorders, individuals with ARG1-D usually appear healthy at birth and hyperammonemia is comparatively less severe and less common. Clinical manifestations typically begin to develop in early childhood in association with high plasma arginine levels, with hyperargininemia (and not hyperammonemia) considered to be the primary driver of disease sequelae. Nearly five decades of clinical experience with ARG1-D and empirical studies in genetically manipulated models have generated a large body of evidence that, when considered in aggregate, implicates arginine directly in disease pathophysiology. Severe dietary protein restriction to minimize arginine intake and diversion of ammonia from the urea cycle are the mainstay of care. Although this approach does reduce plasma arginine and improve patients' cognitive and motor/mobility manifestations, it is inadequate to achieve and maintain sufficiently low arginine levels and prevent progression in the long term. This review presents a comprehensive discussion of the clinical and scientific literature, the effects and limitations of the current standard of care, and the authors' perspectives regarding the past, current, and future management of ARG1-D.arginase deficiency, guanidino compounds, hyperargininemia, inborn error of metabolism, urea cycle disorder Synopsis ARG1-D is a distinct urea cycle disorder with a progressive neurologic phenotype. This review presents a comprehensive discussion of evidence from genetically manipulated mouse models and observations from clinical practice that implicate high arginine levels directly in disease pathophysiology.

Efficacy and safety of pegzilarginase in arginase 1 deficiency (PEACE): a phase 3, randomized, double-blind, placebo-controlled, multi-centre trial

“…Normalization of pArg was previously unachievable with current standard-of-care, as reflected by the multiple-fold elevation of pArg in the trial cohort at baseline and extensive documentation in the literature. 1 , 3 , 6 , 9 , 10 , 15…”

“…1 , 2 Plasma arginine (pArg) levels are persistently elevated, 1 , 3 , 4 leading to progressive and debilitating neurologic manifestations. 1 , 5 , 6 , 7 , 8 , 9 , 10 ARG1-D presents with a distinct neurologic phenotype compared with other urea cycle disorders. 1 , 11 , 12 After uneventful neonatal period, clinical symptoms typically become apparent during first years of life, and worsen with cumulative exposure to high pArg and its metabolites, guanidino compounds (GCs).…”

“…1 , 5 , 6 , 7 , 8 , 9 , 10 ARG1-D presents with a distinct neurologic phenotype compared with other urea cycle disorders. 1 , 11 , 12 After uneventful neonatal period, clinical symptoms typically become apparent during first years of life, and worsen with cumulative exposure to high pArg and its metabolites, guanidino compounds (GCs). 1 , 9 The hallmark feature of ARG1-D is prominent and progressive lower-limb spasticity leading to gait abnormalities, difficulty walking and climbing stairs, and need for assistive devices.…”

Complete genome analysis of Bacillus subtilis derived from yaks and its probiotic characteristics

“…Amino acids are the basic constituent unit of proteins, which play key roles in energy conversion, protein biosynthesis and protein biosynthesis ( 47 ). For instance, arginine can participate in the ornithine cycle and convert the ammonia produced in the body into non-toxic urea through the ornithine cycle, thereby decreasing the blood ammonia concentration ( 48 ). Serine has been demonstrate to possess several metabolic functions including providing precursors for the synthesis of phosphoglycerides, neurotransmitters, sphingolipids, proteins and phosphatidylserine ( 49 , 50 ).…”

Generating an efficient arginase variant for medical and industrial uses: In Silico engineering

“…Indeed, no licensed therapeutic for this enzyme deficiency was approved to date albeit a clinical trial experimenting pegzilarginase as a replacement therapy is being undertaken [18]. This force medical care practitioners to focus only on controlling arginine levels for managing this rare condition [19].…”